Exertion induced heat exhaustion is the second most common cause of death following head and spinal injuries among American athletes. Moreover, classical heat stroke killed hundreds of people in the USA and Greece during the heat waves of 1987. The pathophysiology of this disorder remains obscure, but the preeminent role of the cardiovascular system is well recognized. At a recent international workshop on heat stroke it was recommended that animal models be developed to specifically investigate blood flow distribution to the liver, kidney, skin, and CNS during hyperthermia. We established such a model 3 years ago and based on our current findings we hypothesize that hyperthermia causes cardiovascular insufficiency and that the fatal mechanism in heat stroke involves the selective loss of splanchnic vascular control. This proposal continues to focus on systemic mechanisms of vascular control and begins to explore the tissue mechanisms involved. Our specific aims are to evaluate (a) if splanchnic vasoconstriction in the hyperthermic rat produces mucosal lesions in the small intestine, increases capillary permeability, and causes endotoxemia leading to hypotension; (b) survivability, (c) the role of cardiopulmonary baroreflexes, oxygen radicals, endotoxins, and neurohumoral mechanisms in mediating the changes in splanchnic vascular resistance during hyperthermia; and (d) the effects of training and heat acclimation on the circulatory response to hyperthermia. We also plan to identify the vessels within the microcirculation, in vivo, that contribute to splanchnic vascular resistance and to establish an isolated vessel preparation that will enable us to determine (a) at what temperature resistance vessels dilate, (b) the role of the vascular endothelium in mediating the reduction in splanchnic resistance in the heat-stressed animal, and (c) if receptor sensitivity to NE is significantly altered by hyperthermia. In vivo measurements will include renal, superior mesenteric, and caudal artery blood flows, mean arterial pressure, heart rate, core body temperature, and internal dimensions of 1st, 2nd, and 3rd order arterioles within the intestinal vasculature. In vitro measurements on isolated vessels will include pressure and dimensional analysis on vessels with and without their endothelium intact. In specific protocols, we will also measure sympathetic nerve activity, the osmotic reflection coefficient, and endotoxins levels in the plasma. The significance of this research lies in its contribution to understanding basic mechanisms underlying heat stroke and shock syndromes produced by hypovolemia. Thus, the information generated by this research has application to numerous clinical problems.